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A physiologically based pharmacokinetic model of clopidogrel in populations of European and Japanese ancestry: An evaluation of CYP2C19 activity.

Authors :
Duong JK
Nand RA
Patel A
Della Pasqua O
Gross AS
Source :
Pharmacology research & perspectives [Pharmacol Res Perspect] 2022 Apr; Vol. 10 (2), pp. e00946.
Publication Year :
2022

Abstract

Treatment response to clopidogrel is associated with CYP2C19 activity through the formation of the active H4 metabolite. The aims of this study were to develop a physiologically based pharmacokinetic (PBPK) model of clopidogrel and its metabolites for populations of European ancestry, to predict the pharmacokinetics in the Japanese population by CYP2C19 phenotype, and to investigate the effect of clinical and demographic factors. A PBPK model was developed and verified to describe the two metabolic pathways of clopidogrel (H4 metabolite, acyl glucuronide metabolite) for a population of European ancestry using plasma data from published studies. Subsequently, model predictions in the Japanese population were evaluated. The effects of CYP2C19 activity, fluvoxamine coadministration (CYP2C19 inhibitor), and population-specific factors (age, sex, BMI, body weight, cancer, hepatic, and renal dysfunction) on the pharmacokinetics of clopidogrel and its metabolites were then characterized. The predicted/observed ratios for clopidogrel and metabolite exposure parameters were acceptable (twofold acceptance criteria). For all CYP2C19 phenotypes, steady-state AUC <subscript>0-τ</subscript> of the H4 metabolite was lower for the Japanese (e.g., EM, 7.69 [6.26-9.45] ng·h/ml; geometric mean [95% CI]) than European (EM, 24.8 [20.4-30.1] ng·h/ml, p < .001) population. In addition to CYP2C19-poor metabolizer phenotype, fluvoxamine coadministration, hepatic, and renal dysfunction were found to reduce H4 metabolite but not acyl glucuronide metabolite concentrations. This is the first PBPK model describing the two major metabolic pathways of clopidogrel, which can be applied to populations of European and Japanese ancestry by CYP2C19 phenotype. The differences between the two populations appear to be determined primarily by the effect of varying CYP2C19 liver activity.<br /> (© 2022 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Details

Language :
English
ISSN :
2052-1707
Volume :
10
Issue :
2
Database :
MEDLINE
Journal :
Pharmacology research & perspectives
Publication Type :
Academic Journal
Accession number :
35307978
Full Text :
https://doi.org/10.1002/prp2.946